Glutamate-induced internalization of Ca(v)1.3 L-type Ca(2+) channels protects retinal neurons against excitotoxicity

• Published in: The Journal of physiology Vol. 588; no. Pt 6; p. 953
• Main Authors: Mizuno, Fengxia, Barabas, Peter, Krizaj, David, Akopian, Abram
• Format: Journal Article
• Language: English
• Published: England 15.03.2010
• Subjects: Animals; Calcium Channels, L-Type - metabolism; Caudata; Cytoskeleton - physiology; Dynamins - metabolism; Electrophysiological Phenomena - physiology; Feedback, Physiological - physiology; Glutamic Acid - adverse effects; Glutamic Acid - pharmacology; Patch-Clamp Techniques; Receptors, Glutamate - drug effects; Receptors, Glutamate - metabolism; Retinal Neurons - cytology; Retinal Neurons - drug effects; Retinal Neurons - metabolism
• ISSN: 1469-7793; 1469-7793
• DOI: 10.1113/jphysiol.2009.181305

Glutamate-induced rise in the intracellular Ca(2+) level is thought to be a major cause of excitotoxic cell death, but the mechanisms that control the Ca(2+) overload are poorly understood. Using immunocytochemistry, electrophysiology and Ca(2+) imaging, we show that activation of ionotropic glutamate receptors induces a selective internalization of Ca(v)1.3 L-type Ca(2+) channels in salamander retinal neurons. The effect of glutamate on Ca(v)1.3 internalization was blocked in Ca(2+)-free external solution, or by strong buffering of internal Ca(2+) with BAPTA. Downregulation of L-type Ca(2+) channel activity in retinal ganglion cells by glutamate was suppressed by inhibitors of dynamin-dependent endocytosis. Stabilization of F-actin by jasplakinolide significantly reduced the ability of glutamate to induce internalization suggesting it is mediated by Ca(2+)-dependent reorganization of actin cytoskeleton. We showed that the Ca(v)1.3 is the primary L-type Ca(2+) channel contributing to kainate-induced excitotoxic death of amacrine and ganglion cells. Block of Ca(v)1.3 internalization by either dynamin inhibition or F-actin stabilization increased vulnerability of retinal amacrine and ganglion cells to kainate-induced excitotoxicity. Our data show for the first time that Ca(v)1.3 L-type Ca(2+) channels are subject to rapid glutamate-induced internalization, which may serve as a negative feedback mechanism protecting retinal neurons against glutamate-induced excitotoxicity.